The lung airways form through a reiterative process of branching morphogenesis with concomitant cellular differentiation that is regulated, in part, through the activity of multiple signal transduction pathways. Accumulating evidence points to a role for both positive and negative signals from these pathways, which are regulated in a spatial and temporal manner during lung morphogenesis. The action of these pathways results in the distinct proximal-distal patterning observed in the lung airways, which is essential for the proper differentiation of airway epithelia into the active gas exchange interface in mammals. We have recently demonstrated a critical role for the Wnt signaling pathway in lung airway development and differentiation. Our studies show that inactivation of Wnt7b results in severe lung hypoplasia resulting from inhibited airway branching as well as defects in mesenchymal proliferation and type I cell differentiation. We have more recently demonstrated that inactivation of the canonical Wnt pathway in lung epithelia either by loss of (-catenin expression or expression of the Wnt inhibitor dkk1 leads to a loss of distal airway epithelium by acting upstream of essential transcriptional and signaling factors including N-myc, BMP4 and FGF signaling. Furthermore, we have identified the co-receptor complex in lung epithelium that transmits canonical Wnt signals through Wnt7b. Our hypothesis is that Wnt signaling plays a critical role in embryonic lung airway development, primarily through controlling patterning and differentiation of the airway epithelium. Since much is still not understood about the basic mechanisms underlying Wnt signaling in lung epithelial differentiation and development, we propose to further define the role of Wnt signaling by 1) determining the underlying in vivo mechanism involved in canonical Wnt signalings role in proximal-distal airway petterning, 2) determine the role of non-canonical Wnt signaling in the regulation of lung airway morphogenesis and differentiation, and 3) define the cellular mechanism by which both canonical and non-canonical Wnt signaling regulates lung epithelial cell differentiation, motility, and growth. These aims will address the where, why, and how Wnt signaling controls lung epithelial development, which is critical to a better understanding of how defective lung epithelial differentiation leads to human disease. Project narrative: Lung disease is a leading cause of death and morbidity in both neonates and adults. Understanding the molecular mechanisms that drive lung epithelial differentiation will allow for better design of future therapies for lung diseases. The current proposal uses novel state-of-the-art genetic models to determine the role of the Wnt signal transduction pathway in regulating lung epithelial differentiation with the ultimate goal of determining whether this pathway is a potential target of therapeutic intervention.